A trial of gantenerumab or solanezumab in dominantly inherited Alzheimer's disease

Abstract

Dominantly inherited Alzheimer's disease (DIAD) causes predictable biological changes decades before the onset of clinical symptoms, enabling testing of interventions in the asymptomatic and symptomatic stages to delay or slow disease progression. We conducted a randomized, placebo-controlled, multi-arm trial of gantenerumab or solanezumab in participants with DIAD across asymptomatic and symptomatic disease stages. Mutation carriers were assigned 3:1 to either drug or placebo and received treatment for 4-7 years. The primary outcome was a cognitive end point; secondary outcomes included clinical, cognitive, imaging and fluid biomarker measures. Fifty-two participants carrying a mutation were assigned to receive gantenerumab, 52 solanezumab and 40 placebo. Both drugs engaged their Aβ targets but neither demonstrated a beneficial effect on cognitive measures compared to controls. The solanezumab-treated group showed a greater cognitive decline on some measures and did not show benefits on downstream biomarkers. Gantenerumab significantly reduced amyloid plaques, cerebrospinal fluid total tau, and phospho-tau181 and attenuated increases of neurofilament light chain. Amyloid-related imaging abnormalities edema was observed in 19.2% (3 out of 11 were mildly symptomatic) of the gantenerumab group, 2.5% of the placebo group and 0% of the solanezumab group. Gantenerumab and solanezumab did not slow cognitive decline in symptomatic DIAD. The asymptomatic groups showed no cognitive decline; symptomatic participants had declined before reaching the target doses.

Fig. 1 |. Randomization, group assignment and follow-up.

There were no significant between-group differences in the reasons for trial discontinuation; the most common reason was disease progression. Noncarriers were assigned to placebo and their data were not used in the reported study analyses. Those who chose to learn their mutation status were automatically discontinued from the trial. Thirty-nine participants discontinued: 61.6% due to withdrawal by participant or their proxy (13 due to disease progression, 5 to trial-related burden, 6 other); 33.3% due to physician decision (7 due to disease progression, 6 due to AEs/met protocol discontinuation criteria); 5.1% other. ITT, intention to treat; mITT, modified ITT.

Fig. 2 |. Cognitive and clinical results.

Estimated mean change from baseline with 95% confidence intervals for treatment and pooled placebo groups using MMRM analyses. a, Digit Symbol scores range from 0 to 93, with lower scores indicating poorer cognitive performance. b, MMSE scores range from 0 to 30, with lower scores indicating poorer cognitive performance. c, Logical Memory scores range from 0 to 25, with lower scores indicating poorer cognitive performance. d, ISLT Delayed Recall scores range from 0 to 12, with lower scores indicating poorer cognitive performance. e, CDR-SB scores range from 0 to 18, with higher scores indicating worse cognition and daily function. f, FAS scores range from 0 to 30, with higher scores indicating worse instrumental activities of daily living. The sample sizes at yearly assessments are listed below the x axes. Mean values and statistics are shown in Supplementary Table 1. Note that the primary analysis used the DIAN–MCE. *P < 0.05 for solanezumab versus shared placebo.

Fig. 3 |. Key biomarker results.

Estimated mean change from baseline with 95% confidence intervals for the treatment and shared placebo groups using MMRM analyses. a, Estimated mean change from baseline in brain amyloid burden for gantenerumab measured by the average SuVR of cortical regions of interest (superior frontal, rostral middle frontal, superior temporal, middle temporal, lateral orbitofrontal, medial orbitofrontal and precuneus), assessed by PiB-PET. The transformation of SuVR to Centiloid is shown in Supplementary Fig. 4. b, Estimated mean change from baseline in CSF total Aβ₄₂ (free + bound) for solanezumab. c,d, Estimated mean change from baseline in CSF phospho-tau181 for gantenerumab (c) and solanezumab (d), respectively. e,f, Estimated mean change from baseline in CSF total tau for gantenerumab (e) and solanezumab (f), respectively. g,h, Estimated mean change from baseline in CSF NfL (pg ml⁻¹, log-transformed) for gantenerumab (g) and solanezumab (h), respectively. Sample sizes at yearly assessments are listed below the x axes. Mean values and statistics are shown in Supplementary Tables 2 and 3. Each drug group was compared to the shared placebo group independently using the MMRM model. *P < 0.05, **P < 0.01, ***P < 0.001.